Efficacy of Exercise on Muscle Function and Physical Performance in Older Adults with Sarcopenia: An Updated Systematic Review and Meta-Analysis

This study aimed to analyze the efficacy of exercise interventions on muscle strength, muscle mass, and physical performance in older adults with sarcopenia. Randomized controlled studies assessing exercise effects on sarcopenia were searched in Web of Science, PubMed, Cochrane Library, ProQuest, EBSCOhost, Scopus, EMBASE, and VIP and CNKI up to 31 March 2022. Data were expressed as weighted/standardized mean difference (MD/SMD) with 95% confidence intervals (CI). I2 index was employed for heterogeneity. The initial search identified 5379 studies, and 23 studies involving 1252 participants met the inclusion criteria for further analysis. Results revealed that exercise interventions can significantly improve grip strength (MD = 2.38, 95%CI = 1.33–3.43), knee extension strength (SMD = 0.50, 95%CI = 0.36–0.64), muscle mass of lower extremities (MD = 0.28, 95%CI = 0.01–0.56), walking speed (SMD = 0.88, 95%CI = 0.49–1.27), and functional mobility (MD = −1.77, 95%CI = −2.11–−1.42) among older adults with sarcopenia. No significant exercise effects were found on fat-free muscle mass, appendicular muscle mass, skeletal muscle mass, and muscle mass of the upper extremities. The results of subgroup analysis indicated that both resistance training and multicomponent exercise could significantly increase the muscle strength, while aerobic exercise did not. The findings suggest that exercise intervention can effectively improve muscle function and physical performance in older adults with sarcopenia, but has limited effects on the muscle mass of the upper extremities. In addition, it is highly recommended to apply group-based and supervised resistance training and multicomponent exercise in the prevention and treatment of sarcopenia among the older population.


Introduction
The remarkable increase in life expectancy and decrease in fertility rates result in an expanding ageing population worldwide. Because of ageing-related functional reduction, the wellbeing of older adults has been a focus for ageing-related research. A fact related to the advancing age is that older adults tend to have a sedentary lifestyle [1], which finally accelerates the loss of degradation of skeletal muscle mass and physical function.
Sarcopenia, as a critical component of frailty syndrome, refers to the progressive and generalized skeletal muscle disorder that involves the accelerated loss of muscle mass and function [2,3]. People with sarcopenia have been reported with declines in muscle strength and muscular functioning, which may ultimately lead to physical disability, reduced quality of life, and even death [4,5]. Although there are conflicting opinions about the diagnosis of sarcopenia, muscle strength, muscle mass, and physical functioning are the core diagnostic criteria for sarcopenia [6]. The accumulated evidence has indicated that sarcopenia is

Search Strategy
We systematically searched the related randomized controlled trials (RCT) by implying exercise as the primary intervention among older adults with sarcopenia in the following databases, Web of Science, PubMed, Cochrane Library, ProQuest, EBSCOhost, Scopus, EMBASE, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) from inception to 31 March 2022. The following MeSH terms were searched in English and Chinese: randomized controlled trial, sarcopenia, exercise, muscle function, physical performance, older adult, and the related terms used in their broadest sense. The detailed search strategies are described in Supplementary Material.

Eligibility Criteria
Inclusion criteria: (i) full-text published in English or Chinese; (ii) RCTs; (iii) taking exercise as the single intervention component in one group; (iv) participants were identified with sarcopenia; (v) participants aged 60 years and above; and (vi) primary outcomes include muscle function and physical performance indicators.

Study Selection and Data Collection
After removing the duplications, two researchers independently screened the study titles and abstracts. Then the full-text reviews were conducted with data extraction. Gray literature was explored by reviewing reference lists of selected primary studies and the related systematic reviews. Disagreements between the two researchers were resolved by consensus or a third researcher. The data included authors, publication year, sex, age, sample size, exercise interventions (types and intensity), and outcome measures. In cases of missing valuable data or information, the corresponding authors of these studies were contacted.

Risk of Bias Assessment
The methodological quality of the included studies was assessed using the Cochrane Collaboration risk of bias tool [20], which includes bias in selection (randomization and allocation), performance, detection, attrition, reporting, and other components. Two researchers performed the assessment independently, and the third researcher was consulted for resolution whenever discrepancies existed.

Statistical Analysis
The data analysis was performed using statistical software of the Cochrane Collaboration Review Manager (RevMan, version 5.3, Copenhagen, Denmark). Sample size, means, and standard deviations (SDs) were extracted for each RCT arm. The I 2 statistic was used to describe the percentage of total variation across studies due to heterogeneity rather than chance [21]. A fixed-effect model was used to pool the results if the heterogeneity was not significant (I 2 < 50%), and the random-effect model was applied when I 2 > 50% [22]. Sensitivity analysis was carried out by removing studies one by one [23], and the subgroup analysis was performed for studies with high heterogeneity. Under the fix-model analysis, the weighted mean difference (MD) was used to assess the measure of effect, and the standardized mean difference (SMD) was applied if there were different outcome measures [24]. Finally, the STATA version 16 was used to assess the publication bias through the funnel plots and Egger test [25]. The statistical significance level was set at p < 0.05.

Search Results
A total of 5379 studies were found in the initial search, from which 3335 duplications were removed, and 1948 records were removed for other reasons. Ninety-one studies were reviewed in full text, and 23 RCT studies involving 30 comparisons were included in this systematic review and meta-analysis ( Figure 1).

Summary of Risk of Bias
For the selection bias, all studies reported how random sequences were generated, and 10 of 23 trials reported the allocation concealment [15,26,27,33,[36][37][38][39]41,45]. Twentytwo studies did not conceal the research purpose to the participants, and one study [40] did not mention whether informed consent was signed or not. Therefore, there is a high

Summary of Risk of Bias
For the selection bias, all studies reported how random sequences were generated, and 10 of 23 trials reported the allocation concealment [15,26,27,33,[36][37][38][39]41,45]. Twenty-two studies did not conceal the research purpose to the participants, and one study [40] did not mention whether informed consent was signed or not. Therefore, there is a high risk of performance bias in these studies and this is the common problem in exercise interventions since blinding participants from exercise groups is quite difficult. Only five studies blinded the outcome assessment to participants [16,[36][37][38]41], and 18 studies had a high risk of detection bias. In the two studies [16,26], a large number of subjects were lost in the experimental process, but the specific reasons were not reported, so there was a high risk of attrition bias. In addition, all studies had low risk regarding reporting bias and other biases. The detailed information can be found in Figure 2. risk of performance bias in these studies and this is the common problem in exercise interventions since blinding participants from exercise groups is quite difficult. Only five studies blinded the outcome assessment to participants [16,[36][37][38]41], and 18 studies had a high risk of detection bias. In the two studies [16,26], a large number of subjects were lost in the experimental process, but the specific reasons were not reported, so there was a high risk of attrition bias. In addition, all studies had low risk regarding reporting bias and other biases. The detailed information can be found in Figure 2.

Effects of Exercise on Muscle Function and Physical Performance
Muscle function is the primary outcome of this study, and it includes muscle strength (i.e., grip strength and knee extension strength) and muscle mass (i.e., muscle mass of lower extremities, free fat mass, skeletal muscle mass, appendicular muscle mass, and muscle mass of upper extremities). The secondary outcome is physical performance, including walking speed and functional mobility as tested using the TUG.

Grip Strength
A total of 17 studies involving 954 participants had taken grip strength as one of the main outcomes. A relatively high level of heterogeneity was present among different studies (I 2 = 57.0%), and the sensitivity analysis indicated that removing any one study cannot lower the heterogeneity. The high heterogeneity may be due to different types of exercise formats. Resistance training was used in nine studies, aerobic training was applied in five studies, and multicomponent training was adopted in seven. Subgroup analysis was performed (Figure 3a), and the results demonstrated that exercise format is the main source of heterogeneity (I 2 = 56%, p < 0.001). The intra-group heterogeneity was low in each of the three exercise formats (RT: I

Effects of Exercise on Muscle Function and Physical Performance
Muscle function is the primary outcome of this study, and it includes muscle strength (i.e., grip strength and knee extension strength) and muscle mass (i.e., muscle mass of lower extremities, free fat mass, skeletal muscle mass, appendicular muscle mass, and muscle mass of upper extremities). The secondary outcome is physical performance, including walking speed and functional mobility as tested using the TUG.

Grip Strength
A total of 17 studies involving 954 participants had taken grip strength as one of the main outcomes. A relatively high level of heterogeneity was present among different studies (I 2 = 57.0%), and the sensitivity analysis indicated that removing any one study cannot lower the heterogeneity. The high heterogeneity may be due to different types of exercise formats. Resistance training was used in nine studies, aerobic training was applied in five studies, and multicomponent training was adopted in seven. Subgroup analysis was performed (Figure 3a), and the results demonstrated that exercise format is the main source of heterogeneity (I 2 = 56%, p < 0.001). The intra-group heterogeneity was

Knee Extension Strength
Eight studies involving 620 participants applied knee extension strength as the outcome. Since the measures of knee extension were different (isometric measures vs. isokinetic measures), the SMD was applied to calculate the effect size, and a low level of heterogeneity was found (I 2 = 12%). Results of the meta-analysis indicated that exercise intervention can significantly improve muscle strength for knee extension (SMD = 0.50, 95%CI = 0.36-0.64, p < 0.001) (Figure 4a).

Knee Extension Strength
Eight studies involving 620 participants applied knee extension strength as the outcome. Since the measures of knee extension were different (isometric measures vs. isokinetic measures), the SMD was applied to calculate the effect size, and a low level of heterogeneity was found (I 2 = 12%). Results of the meta-analysis indicated that exercise intervention can significantly improve muscle strength for knee extension (SMD = 0.50, 95%CI = 0.36-0.64, p < 0.001) (Figure 4a).
In order to evaluate the effect of different exercise formats on knee extension strength in older adults with sarcopenia, a subgroup analysis was performed. Results showed that significant and positive effects of both resistance training (SMD = 0.84, 95%CI = 0. 43 (Figure 4b).

Muscle Mass
Eleven studies involving 648 participants set muscle mass as the main outcome, including muscle mass of lower extremities, free fat mass, skeletal muscle mass, appendicular muscle mass, and muscle mass of upper extremities. Results from sensitivity analysis indicated low heterogeneity among different studies (I 2 = 0). Hence, the effect size was estimated using the fixed-effects model, and the results revealed significant exercise effects on the muscle mass of lower extremities (MD = 0.28, 95%CI = 0.01-0.56, p = 0.04) (Figure 5a), and limited effects were found in other muscle mass indicators of older adults with sarcopenia (Figure 5b-e).

Muscle Mass
Eleven studies involving 648 participants set muscle mass as the main outcome, including muscle mass of lower extremities, free fat mass, skeletal muscle mass, appendicular muscle mass, and muscle mass of upper extremities. Results from sensitivity analysis indicated low heterogeneity among different studies (I 2 = 0). Hence, the effect size was estimated using the fixed-effects model, and the results revealed significant exercise effects on the muscle mass of lower extremities (MD = 0.28, 95%CI = 0.01-0.56, p = 0.04) (Figure 5a), and limited effects were found in other muscle mass indicators of older adults with sarcopenia (Figure 5b,e).

Walking Speed
There were 14 studies involving 872 participants that applied walking speed as the outcome. The study heterogeneity is quite big (I 2 = 85%). Subgroup analysis of three different exercise types showed high heterogeneity within each exercise format (I 2 > 80%). This would be related to the fact that big variations exist in test procedures and requirements. Among these studies, different walking distances were used including 4 m [27], 5 m [38], 6 m [14], 10 m [15,16,45], and 400 m [44]. Some studies also assessed walking speed by calculating walking distance in 10 min [39]. Inconsistencies also exist in starting position (static vs. dynamic) and whether or not to emphasize the ending point. The effect size of exercise intervention under the random-effects model indicated that exercise could significantly improve the walking speed of older adults with sarcopenia (SMD = 0.88, 95%CI = 0.49-1.27, p < 0.001) (Figure 6a).

Walking Speed
There were 14 studies involving 872 participants that applied walking speed as the outcome. The study heterogeneity is quite big (I 2 = 85%). Subgroup analysis of three different exercise types showed high heterogeneity within each exercise format (I 2 > 80%). This would be related to the fact that big variations exist in test procedures and requirements. Among these studies, different walking distances were used including 4 m [27], 5 m [38], 6 m [14], 10 m [15,16,45], and 400 m [44]. Some studies also assessed walking speed by calculating walking distance in 10 min [39]. Inconsistencies also exist in starting position (static vs. dynamic) and whether or not to emphasize the ending point. The effect size of exercise intervention under the random-effects model indicated that exercise could significantly improve the walking speed of older adults with sarcopenia (SMD = 0.88, 95%CI = 0.49-1.27, p < 0.001) (Figure 6a).

Walking Speed
There were 14 studies involving 872 participants that applied walking speed as the outcome. The study heterogeneity is quite big (I 2 = 85%). Subgroup analysis of three different exercise types showed high heterogeneity within each exercise format (I 2 > 80%). This would be related to the fact that big variations exist in test procedures and requirements. Among these studies, different walking distances were used including 4 m [27], 5 m [38], 6 m [14], 10 m [15,16,45], and 400 m [44]. Some studies also assessed walking speed by calculating walking distance in 10 min [39]. Inconsistencies also exist in starting position (static vs. dynamic) and whether or not to emphasize the ending point. The effect size of exercise intervention under the random-effects model indicated that exercise could significantly improve the walking speed of older adults with sarcopenia (SMD = 0.88, 95%CI = 0.49-1.27, p < 0.001) (Figure 6a).

Functional Mobility
Eight studies involving 364 participants assessed functional mobility using the time up ang go test (TUG). The heterogeneity among these studies was low (I 2 = 27%), and sensitivity analysis showed that the exclusion of any single study had no significant effect on the total effect size. Results from the meta-analysis using the fixed-effect model showed that, in comparison with the placebo group, exercise intervention can improve functional mobility (MD = −1.77, 95%CI = −2.11-−1.42, p < 0.001) (Figure 6b).

Publication Bias
The funnel plot of the knee extension strength was asymmetrical (Supplementary Material). The Egger tests also revealed that there was a relatively higher level of publication bias in knee extension strength (t = 2.11, p = 0.048). The funnel plots of other indicators were symmetrical, and Egger tests also indicated a relatively low level of publication bias (p > 0.05).

Discussion
This meta-analysis of 23 RCT studies assessed the effects of exercise interventions on muscle function and physical performance in older adults with sarcopenia. Results indicated that exercise could effectively improve muscle strength, muscle mass of lower extremities, and physical performance. In addition, resistance and multicomponent exercises would be preferred for muscle strength improvement. Results from this study would enrich the evidence of exercise efficacy in reducing the risks of sarcopenia among older adults.
Muscle strength is an often applied indicator in various diagnostic criteria of sarcopenia [46]. The present results found that moderate resistance training, multicomponent exercises such as aerobic + resistance training [14,26,28,40], resistance + balance + gait training [36,37], and resistance training + outdoor activity [30], would have significant effects on muscle strength for the target population. However, moderate aerobic exercise has shown a limited effect on muscle strength improvement. It has been well documented that resistance training can generate increases in muscle strength [47], whereas aerobic exercise is known to improve cardiorespiratory fitness [48]. In addition, subjective methods such as the self-perceived exertion scale were often used in aerobic exercise to monitor exercise intensity, which would influence the expected quality of aerobic exercise. Compared to multicomponent exercise formats, the single aerobic exercise training may not be interesting and attractive enough; therefore, it would reduce participants' compliance. Regardless of the exercise formats, group exercise with supervision and guidance instead of individual home-based exercise always show better motivation for exercise involvement and more efficacy in muscle strength improvements [27]. It is highly recommended that clinical practice enriches the content of exercise, stimulates exercise interest, and adopts group-based supervised exercise intervention to strengthen the muscle function of older adults with sarcopenia.
The present finding confirmed the positive training effects on muscle mass, especially in the lower body, while Bao and his colleagues found no exercise effect on appendicular skeletal muscle mass [18]. The controversial results would be mainly related to differences in population characteristics. Compared with younger adults, older adults would show a slower physical response to resistance training [49] and gain a lower increment in muscle mass [50][51][52][53]. The muscle mass growth rate depends on the synthesis and degradation rate of proteins [54]. Due to the reduced level of physical activity and the retardation of muscle cell metabolism, the metabolism and synthesis of proteins are degraded among older adults. In addition, the presence of various chronic illnesses, including various inflammatory, respiratory, and endocrinal diseases, would reduce the synthesis rate of proteins in older adults [55]. As discussed above, older adults with sarcopenia have relatively lower levels of physical function and have limited tolerance to high exercise intensity. In addition, it has been well evidenced that exercise intensity significantly affects muscle protein synthesis [56]. All these would finally affect the enhancement of muscle mass amplitude among older adults with sarcopenia.
The present study revealed significant training effects on the muscle mass of lower extremities, which is in line with the findings of the previous related meta-analysis [17]. However, the present study revealed limited effects on the muscle mass of the upper body. This can be explained by the movement features of exercise intervention that tend to emphasize lower body muscle movement. In a study conducted by Kim and his colleagues (2012), the exercise program consisted of repeated toe raises, heel raises, knee lifts, knee extensions, lateral leg raises and leg extensions, hip flexions by resistance bands, but only arms pulling down and biceps bending for the upper body [36]. In addition to the standing posture during exercise intervention, the muscle mass of the lower extremities would receive more exercise stimulations compared to that of the upper body. Further RCT studies are recommended to include more upper body movements to exert substantial training effects on upper body muscle mass.
Walking speed is a commonly used indicator of physical functioning and is highly correlated with falling risks, cognitive ability, and neuromuscular function [57][58][59][60]. Both the Asian Working Group for Sarcopenia Standards (AWGS) and the 2nd Edition of the European Working Group on Sarcopenia Standards (EWGSOP2) include walking speed as the diagnosis criteria of sarcopenia. The results of this study confirm that exercise can effectively increase the walking speed of the target group, which is consistent with previous studies [61][62][63]. However, a relatively higher level of heterogeneity existed among the included studies. This would be mainly related to the differences in walking speed test parameters, such as starting position, walking distance, and the set of the ending points. All these would influence the outcome accuracy [64]. Due to ageing-related functional deterioration, older adults with sarcopenia would require a longer time in signal identification, muscle recruitment, and movement implementation than their age-matched counterparts. Future RCT studies are suggested to apply the standardized walking speed measurement to increase study comparison and reduce study heterogeneity.
There are some limitations in the present study that may comprise the application of study results. First, the quality of the included RCTs was not high, and most studies showed risks of performance bias and detection bias because of the improper application of blinding methods. This would influence the validity of the study results. Second, most studies were conducted on female participants; whether gender differences exist in training effects is unknown. Finally, given the limited number of the included studies, the present findings should be interpreted cautiously when translating into practice.

Conclusions
Exercise can effectively improve muscle function and physical performance in older adults with sarcopenia, but has limited effects on the muscle mass of the upper extremities. In addition, it is highly recommended to apply group-based and supervised resistance training and multicomponent exercise to prevent sarcopenia among the older population.